Phosphatidylserine recognition and Rac1 activation are required for Müller glia proliferation, gliosis and phagocytosis after retinal injury.

Müller glia, the principal glial cell type in the retina, have the potential to reenter the cell cycle after retinal injury. In mammals, proliferation of Müller glia is followed by gliosis, but not regeneration of neurons. Retinal injury is also accompanied by phagocytic removal of degenerated cells. We here investigated the possibility that proliferation and gliosis of Müller glia and phagocytosis of degenerated cells may be regulated by the same molecular pathways. After N-methyl-N-nitrosourea-induced retinal injury, degenerated photoreceptors were eliminated prior to the infiltration of microglia/macrophages into the outer nuclear layer, almost in parallel with cell cycle reentry of Müller glia. Inhibition of microglia/macrophage activation with minocycline did not affect the photoreceptor clearance. Accumulation of lysosomes and rhodopsin-positive photoreceptor debris within the cytoplasm of Müller glia indicated that Müller glia phagocytosed most photoreceptor debris. Pharmacological inhibition of phosphatidylserine and Rac1, key regulators of the phagocytic pathway, prevented cell cycle reentry, migration, upregulation of glial fibrillary acidic protein, and phagocytic activity of Müller glia. These data provide evidence that phosphatidylserine and Rac1 may contribute to the crosstalk between different signaling pathways activated in Müller glia after injury.

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